tbuckley/cabot-search huggingface dataset:
MEDB-12. Severe developmental abnormalities and proliferative cerebellar lesions induced by combined activity of Wnt signalling and loss of SMARCA4
Authors: Carolin Göbel, Dörthe Holdhof, Melanie Schoof, Ulrich Schüller
Journal: Neuro-Oncology (2022)

Abstract Almost all medulloblastomas (MB) of the WNT subgroup are characterized by hotspot mutations in CTNNB1, and mouse models have convincingly demonstrated the tumor-initiating role of these mutations as well as the tumor origin in the dorsal brain stem. Around 20 % of WNT MB additionally carry SMARCA4mutations, but the functional role of these alterations is mostly unknown. We therefore amended previously described Blbp-cre::Ctnnb1(ex3)Fl/+mice by the introduction of a floxed Smarca4 allele. In contrast to existing literature, Blbp-cre::Ctnnb1(ex3)Fl/+ mice had a maximum life span of only 17 days, even after breeding into two different genetic backgrounds (C57BL/6J and 129S2/Sv). The mice displayed a severe developmental phenotype including a thinned cerebral cortex, hydrocephalus, missing cerebellar foliation and layering as well as non-proliferative cell accumulations in brain stem and cerebellum. An additional homozygous loss of SMARCA4 even resulted in prenatal death for most mice and caused big proliferative lesions in the cerebellum at embryonal day 14.5. These lesions appear to originate from SOX2-positive progenitor cells in the cerebellar ventricular zone. In a next experiment, cells isolated from this region will be characterized in vitro and will be transplanted orthotopically to evaluate their neoplastic potential in vivo. Altogether, we hope to elucidate how a loss of SMARCA4 and mutations of Ctnnb1 cooperate during hindbrain development and tumor formation within this region.
Correlation of the expression of microRNA and their predicted targets with prognosis and mortality of penile squamous cell carcinoma
Authors: C.B. Murta, T.K. Furuya, M. Uno, A.G.M. Carrasco, L. Sichero, L.L. Villa, S.F. Faraj, R.F. Coelho, G.B. Guglielmetti, M.D. Cordeiro, K.R.M. Leite, W.C. Nahas, R. Chammas, J. Pontes Jr
Journal: European Urology (2022)
Considerations for Generic-to-Generic Levothyroxine Switching
Authors: Christian Funck-Brentano
Journal: JAMA Internal Medicine (2022)

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Damage-associated molecular patterns (DAMPS) in patients with advanced cancer undergoing systemic treatment.
Authors: Vicente Valenti, Laia Capdevila, Isabel Ruiz, Joan Badia, Francisco Javier Ramos Pascual, Susana Blázquez, Óscar Villuendas, Cristina Pérez, Gemma Flores, Mónica Córdoba, Carlos Alonso
Journal: Journal of Clinical Oncology (2022)

e14524 Background: Immunogenic cell death (ICD) is known for the release of DAMPS from tumor cells. We aimed to find signals of ICD by assessing the variation of plasma DAMPS (HMGB1 and S100A8) after vs. before standard of care (SoC) systemic treatment in patients with advanced solid tumors. Methods: Patients scheduled to start a new line of systemic treatment were included. Plasma concentrations of HMGB1 and S100A8 were measured (ng/mL) before and after three months of treatment. CD44 immunohistochemical (IHC) expression was determined in tumor tissue. After vs. before variation of paired median concentrations was analyzed with the Wilcoxon signed-rank test for the whole population and selected subgroups according to RECIST response, baseline plasmatic iron levels, CD44 expression, and platinum-based treatment. Results: Fifty-two patients were included. The most frequent tumor sites were colorectal (35%) and lung (25%). Forty-two patients (81%) received this treatment as first-line. Thirty-six patients (69%) received chemotherapy (CT) alone, ten (19%) CT plus targeted therapy (7 FOLFOX or XELOX plus bevacizumab, and one each FOLFOX plus cetuximab, FOLFOX plus panitumumab, docetaxel-trastuzumab-pertuzumab), two (3.8%) carboplatin-pemetrexed-pembrolizumab, three (5.8%) pembrolizumab alone and one (1.9%) cetuximab alone. Overall response rate (RECIST) was 42%, rate of patients with low baseline plasmatic iron levels was 53%, and CD44 expression was positive in 35% of the patients. Results on plasma concentration of DAMPS are shown in the table. Conclusions: Signals of ICD were not observed in these patients. HMGB1 variation was not significant while plasma concentration of S100A8 significantly decreased after treatment, more markedly in those patients who experienced tumor response.[Table: see text]
Comparative efficacy and acceptability of cognitive behavioral therapy delivery formats for insomnia in adults: A systematic review and network meta-analysis
Authors: Ya Gao, Long Ge, Ming Liu, Mingming Niu, Yamin Chen, Yue Sun, Ji Chen, Liang Yao, Qi Wang, Zhifan Li, Jianguo Xu, Muyang Li, Liangying Hou, Jiyuan Shi, Kelu Yang, Yitong Cai, Lun Li, Junhua Zhang, Jinhui Tian
Journal: Sleep Medicine Reviews (2022)
The effect of group psychotherapy on quality of life of cancer patients undergoing chemotherapy or endocrine therapy during Covid-19 pandemic: One center experience.
Authors: Mariam Abuladze, Tamar Esakia, Tamta Cholikidze, Ketevani Barabadze, Khatuna Saganelidze
Journal: Journal of Clinical Oncology (2022)

e24133 Background: The announcement of the pandemic by WHO had a great impact on global mental health. Mental disorders like stress, anxiety, depressive symptoms, insomnia, denial, anger, and fear affected the population worldwide. Cognitive-behavioral techniques are effective in improving the control of symptoms, the affective state and coping with the disease. Methods: Female patients were offered to take part in the study by their oncologists. Inclusion criteria included female patients who were diagnosed with cancer during the last 5 years. Intervention included - Online group psychotherapy which was conducted for 3 consecutive months, three times per week, using the interactive ZOOM platform. The Research and Treatment of Cancer (EORTC) quality of life questionnaire QLQ-C30 was used to assess QoL of participants. We asked patients to fill the ERTC questionnaire twice, before the first and after the last psychotherapy sessions. Results: Total of 25 patients aged 18-55 were included in the study, 72% were receiving hormonal therapy, and 28% were receiving chemotherapy. Majority of patients (18) were diagnosed with breast, 4 with cervical and 1 with uterine and 2 with ovarian cancer in last 5 years. All patients were white Caucasian females. Analysis of Variance (ANOVA) showed no difference between groups on pre-RS score; But the study showed significant improvement in post RS (EORTC QLQ-C30) in patients with hormone therapy (Goodness of Fit-R square-0.4471, P-value-0.0024, 95% Confidence Intervals-0.4200 to 1.626), compare to patients with chemotherapy (Goodness of Fit-R square-0.003372, P-value- 0.9016, 95% Confidence Intervals--1.743 to 1.929).All measures were presented as mean with standard deviation and the level of significance was defined as DELTA(D) = 0.05. Conclusions: According to our research, group psychotherapy had a positive effect on quality of life of cancer patients undergoing hormonal therapy and showed no significant impact on patients treated with chemotherapy. More research and a larger sample size is needed for a better interpretation of results.
IMMU-12. Exploring and modulating the tumour immune microenvironment to facilitate the selection of immunotherapies for paediatric-type diffuse high-grade glioma
Authors: Julia Cockle, Lynn Bjerke, Alan Mackay, Yura Grabovska, Anna Burford, Valeria Molinari, Rita Pereira, Jessica Boult, Simon Robinson, Diana Martins Carvalho, Matthew Clarke, Ian Titley, Erika Yara, Karin Straathof, Erik Wennerberg, Oren Becher, Maria Castro, Alan Melcher, Chris Jones
Journal: Neuro-Oncology (2022)

Abstract Immune cells have the potential to selectively eradicate high-risk brain tumours such as paediatric-type diffuse high-grade glioma (PDHGG). We aim to characterize the tumour immune microenvironment (TIME) of intra-cranial syngeneic mouse models of diffuse hemispheric glioma, H3G34 (DHG-H3G34) and diffuse midline glioma, H3K27 (DMG-H3K27). We also demonstrate how an oncolytic reovirus (Reolysin) can “heat-up” the TIME of our syngeneic models. Orthotopic immunocompetent mouse models of DHG-H3G34 (C57BL/6, NRASG12V + shp53 + shATRX +/- H3.3G34R) and DMG-H3K27 (Nestin-Tv-a/p53fl/fl, RCAS-ACVR1R206H + RCAS-H3.1K27M) were profiled using single-cell RNA-sequencing (scRNA-seq) (10x genomics), a 22-colour custom flow cytometry immune panel and spatial transcriptomics. Differential marker expression was validated with immunohistochemistry and immunofluorescence in tissue sections. Syngeneic mouse tumours treated systemically with Reolysin were also profiled to evaluate the effects of the oncolytic virus on the TIME. Cell type predictions in scRNA-seq using singleR, ssGSEA and expression of individual marker genes suggested that the predominant immune cell types within hemispheric tumours were monocytes (11-21%) and macrophages (10-19%) with much smaller proportions of CD4+ and CD8+ T-cells (4-10%). By contrast, much smaller proportions of monocytes (2%) and macrophages (3%) were observed in the H3.1K27M pontine model. Flow cytometry, immunohistochemistry and immunofluorescence validated scRNA-seq immune profiles and characterised signalling of the PD-1/PD-L1 checkpoint pathway. Spatial transcriptomics allowed immune cell populations to be positioned within tumour sections and showed significant co-localization of CD4+ and CD8+ lymphocytes at tumour margins. Treatment of syngeneic mouse tumours with Reolysin resulted in reduced tumour volumes and altered the TIME, in particular increasing cytotoxic T-cell tumour infiltration. Our results highlight immunological heterogeneity within molecular subgroups of PDHGG and demonstrate ability of a systemically delivered oncolytic virus, Reolysin, to “heat-up” the TIME, contributing to a more immune actionable profile. Future work will help to identify optimal combinations for the next generation of immunotherapies in PDHGG.
ATRT-01. Reconstitution of cGAS/ STING pathway via epigenetic reprogramming leads to anti-viral inflammatory signaling in Atypical teratoid rhabdoid tumors (ATRTs)
Authors: Avani Mangoli, Seetha Hariharan, David Ashley, Rebecca Fuller, Michelle Bowie, Aaron Briley, Michael Brown, Janell Hostettler
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Atypical teratoid rhabdoid tumors (ATRTs) are highly aggressive brain tumors that affect young children characterized by biallelic inactivation of the SMARCB1 gene. Though patients benefit from multimodal therapy, there is no improvement in overall survival which necessitates the exploration of alternative approaches. Innate-based immune and epigenetic therapies have shown benefits in several cancers. The role of innate immune signaling has not been investigated in ATRTs. Our previous data from several ATRT cell lines showed loss of expression of key innate signaling components, like cGAS and STING that are needed for sensing extracellular dsDNA. Additionally, ATRT cell lines do not respond to STING agonists, like cGAMP or ISD. RESULTS: Co-treatment of ATRT cell lines, BT-12 and BT-16 with two epigenetic modulators, panobinostat and decitabine, leads to re-expression of cGAS and STING in a time-dependent manner. Furthermore, treatment with decitabine alone leads to demethylation of several CpG sites on the STING promoter and increased expression of STING mRNA. Panobinostat and decitabine co-treatment reconstitute STING-mediated innate signaling, as measured by IRF-3 and STAT1 phosphorylation and production of ISG-15 and IFIT-1 after treatment with cGAMP, a STING agonist. Co-treatment with panobinostat and decitabine also induced expression of antiviral pro-inflammatory chemokines/cytokines in ATRT cell lines, including type III IFN, IL-6, IL-8, IL-28, and IL-29. CONCLUSION: Our data suggest that ATRT cell lines are unresponsive to innate agonists possibly due to the loss of expression of key innate immune components. However, the cGAS/STING pathway is reactivated by epigenetic drugs, specifically the combination of panobinostat and decitabine. This is further potentiated by treating with STING agonists like cGAMP. Combination treatment of ATRT cell lines with panobinostat and decitabine also induced antiviral inflammatory signaling. This response could be a potential treatment modality to inhibit tumor growth and/or mediate cancer immunotherapy in these aggressive tumors.
<i>PHACTR1</i>modulates vascular compliance but not endothelial function: a translational study
Authors: Alice Wood, Alexios Antonopoulos, Surawee Chuaiphichai, Theodosios Kyriakou, Rebeca Diaz, Abtehale Al Hussaini, Anna-Marie Marsh, Manjit Sian, Mitul Meisuria, Gerry McCann, Victoria S Rashbrook, Edward Drydale, Sally Draycott, Murray David Polkinghorne, Ioannis Akoumianakis, Charalambos Antoniades, Hugh Watkins, Keith M Channon, David Adlam, Gillian Douglas
Journal: Cardiovascular Research (2022)

Abstract Aims The non-coding locus at 6p24 located in Intron 3 of PHACTR1 has consistently been implicated as a risk allele in myocardial infarction and multiple other vascular diseases. Recent murine studies have identified a role for Phactr1 in the development of atherosclerosis. However, the role of PHACTR1 in vascular tone and in vivo vascular remodelling has yet to be established. The aim of this study was to investigate the role of PHACTR1 in vascular function. Methods and results Prospectively recruited coronary artery disease (CAD) patients undergoing bypass surgery and retrospectively recruited spontaneous coronary artery dissection (SCAD) patients and matched healthy volunteers were genotyped at the PHACTR1 rs9349379 locus. We observed a significant association between the PHACTR1 loci and changes in distensibility in both the ascending aorta (AA = 0.0053 ± 0.0004, AG = 0.0041 ± 0.003, GG = 0.0034 ± 0.0009, P &amp;lt; 0.05, n = 58, 54, and 7, respectively) and carotid artery (AA = 12.83 ± 0.51, AG = 11.14 ± 0.38, GG = 11.69 ± 0.66, P &amp;lt; 0.05, n = 70, 65, and 18, respectively). This association was not observed in the descending aorta or in SCAD patients. In contrast, the PHACTR1 locus was not associated with changes in endothelial cell function with no association between the rs9349379 locus and in vivo or ex vivo vascular function observed in CAD patients. This finding was confirmed in our murine model where the loss of Phactr1 on the pro-atherosclerosis ApoE−/− background did not alter ex vivo vascular function. Conclusion In conclusion, we have shown a role for PHACTR1 in arterial compliance across multiple vascular beds. Our study suggests that PHACTR1 has a key structural role within the vasculature.
A phase 1/2 study of REGN4336, a PSMAxCD3 bispecific antibody, alone and in combination with cemiplimab in patients with metastatic castration-resistant prostate cancer.
Authors: William Kevin Kelly, Pradeep Thanigaimani, Furong Sun, Frank A. Seebach, Israel Lowy, Sabina Sandigursky, Elizabeth Miller
Journal: Journal of Clinical Oncology (2022)

TPS5105 Background: Prostate cancer is the leading cause of new cancer diagnoses and the second most common cause of cancer-related death in American men. Prognosis is especially poor for men with metastatic castration resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA) is highly expressed on malignant prostate tissue but shows limited expression on normal tissue. As such, PSMA is an excellent research target for treatment of mCRPC. REGN4336 is a PSMAxCD3 bispecific antibody designed to facilitate T-cell–mediated killing of PSMA-expressing tumor cells. In preclinical models, REGN4336 demonstrated strong PSMA-dependent antitumor activity that was dose-dependent. Preclinical data also support clinical research into the combination of REGN4336 with cemiplimab (anti–programmed cell death-1) for treating mCRPC. Methods: This is an open-label, Phase 1/2, first-in-human, multicenter dose-escalation study with dose expansion evaluating safety, tolerability, pharmacokinetics (PK), and antitumor activity of REGN4336 administered subcutaneously alone and in combination with intravenous cemiplimab in patients with mCRPC (NCT05125016). Patients must have received at least two prior lines of systemic therapy approved for metastatic and/or castration-resistant disease including a second-generation anti-androgen therapy. In this study, REGN4336 as monotherapy is administered weekly but may be extended to once every 3 weeks following identification of the minimal pharmacologically active dose. REGN4336 in combination with cemiplimab (350 mg) will be administered once every 3 weeks after a 4-week REGN4336 monotherapy lead-in cycle. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or study withdrawal criterion is met. The primary objectives in dose escalation are to evaluate the safety, tolerability, PK, and recommended phase 2 dosing regimen (RP2DR) of REGN4336 alone and in-combination with cemiplimab. Expansion cohort(s) will be enrolled once RP2DRs have been determined. During the expansion phase, the primary objective is to assess clinical activity, as measured by objective response rate with REGN4336 alone or in combination with cemiplimab per modified Prostate Cancer Working Group 3 criteria. At selected sites, PSMA positron emission tomography/computed tomography scans will be performed at predefined timepoints on study. This study is currently open to enrollment. Clinical trial information: NCT03088540.
Patient preferences for treatment and outcomes in hormone-sensitive prostate cancer (HSPC).
Authors: Daniel J. George, Arijit Ganguli, Alicia K. Morgans, Bertrand F. Tombal, Sebastien J. Hotte, Hiroyoshi Suzuki, Hemant Bhadauria, Mok Oh, Charles D. Scales, Kiran Grover, Juan Marcos Gonzalez
Journal: Journal of Clinical Oncology (2022)

e18757 Background: Treatment options for patients with HSPC have broadened, and data regarding patient preferences for therapies can aid in therapeutic decision-making. This study evaluated the impact of attributes associated with therapies for US patients with locally advanced prostate cancer (LAPC) or metastatic HSPC (mHSPC) from the perspective of patient preferences. Methods: An online discrete choice experiment (DCE) was developed for patients with LAPC or mHSPC. The DCE included 12 questions designed to systematically require tradeoffs between treatment attributes of efficacy (5-year overall survival [OS]), tolerability (fatigue, skin rash, neurotoxicity, and common chemotherapy-related toxicity), and convenience (administration factors [route, frequency, and setting], concomitant use of steroids, and monitoring requirements). Respondents could choose androgen deprivation therapy (ADT) alone or with hypothetical therapies that improved 5-year OS but had additional adverse events (AEs). Attribute-specific importance weights measuring their relative impact on treatment choices were estimated using a mixed-logit model, which also controlled for heterogeneity in preferences. Results: From September 3 to October 14, 2021, 82 respondents (mean age 61 years) completed the survey (LAPC, n = 40; mHSPC, n = 42), with 61 (74.4%) receiving ADT at the time of the survey. Respondents reported treatment efficacy (36% [95% confidence interval (CI) 22, 49]) as the most important aspect of treatment choice, followed by changes in chemotherapy-related toxicity (13% [95% CI 3, 22]) and the need for concomitant steroid use (12% [95% CI 5, 19]). Respondents considered monitoring requirements (8% [95% CI 5, 19]) to be more important than fatigue (5% [95% CI 2, 13]). Administration factors were comparable in importance to therapy AEs (Table). Respondents preferred, by at least 10 percentage points, adding therapies to ADT that could improve 5-year OS, at the detriment of additional AEs. Conclusions: After efficacy, convenience was considered to impact treatment choices at a rate comparable to tolerability issues, potentially influenced by perceived COVID-19 exposure risks. Patients with LAPC and mHSPC prioritize efficacy despite the detriment of additional AEs.[Table: see text]
Clinical characteristics of patients with <i>PMS2</i> mutations.
Authors: Samiksha Pandey, Tara Rangarajan, Dana Zakalik
Journal: Journal of Clinical Oncology (2022)

10610 Background: Lynch syndrome is a hereditary cancer predisposition syndrome caused by mutations in mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. The cancer risks and clinical presentation of PMS2 associated Lynch syndrome is not well defined. This study outlines the characteristics of patients with PMS2 mutations identified in a large academic center. Methods: Patients with a pathogenic or likely pathogenic PMS2 variant identified between June 1, 2009 and Dec 31, 2021 were selected from a database at the Nancy and James Grosfeld Cancer Genetics Center at Beaumont Health. Data on demographics, cancer type and molecular testing were retrospectively analyzed. Results: A total of 92 patients from 61 families were found to carry a pathogenic or likely pathogenic variant in PMS2. The mean age at testing was 54 (19 to 95). A majority (50) of the family were Caucasian, while the rest were African American (2), Middle Eastern (2), Multiracial (8). The most common variant was c.137G &gt; T (p.Ser46Ile), seen in twelve of 61 families. Forty-two patients (45.6%) had a personal history of cancer, with a mean age at diagnosis of 63. Of these forty-two patients, four had multiple malignancies, including one patient with six separate cancers. The most common malignancies were breast (16), colon (12), followed by uterine cancer (8), pancreatic (4), prostate (3) and other cancers. The mean age of diagnosis of breast cancer was 56 (41 to 78), colon cancers was 57 (32 to 75), uterine cancer 59 (50 to 72). Tumor IHC was performed in thirteen cases and 11 demonstrated loss of PMS2 protein expression. MSI was performed in 8 cases and 5 were unstable and 3 were stable. Conclusions: This study reveals the the clinical spectrum of cancers in PMS2 related Lynch syndrome. The most common cancers were breast, colon and uterine cancer, with older age of diagnosis. There was evidence of a more severe phenotype, exemplified by a patient with six cancers, suggesting higher penetrance. Further research is needed to better characterize the clinical presentation of PMS2 related Lynch syndrome.